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15-82538986-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate

The NM_001021.6(RPS17):c.156-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

RPS17
NM_001021.6 splice_acceptor

Scores

5
2
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.70
Variant links:
Genes affected
RPS17 (HGNC:10397): (ribosomal protein S17) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S17E family of ribosomal proteins and is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia 4. Alternative splicing of this gene results in multiple transcript variants. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Apr 2014]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 15-82538986-C-T is Pathogenic according to our data. Variant chr15-82538986-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2428499.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPS17NM_001021.6 linkuse as main transcriptc.156-1G>A splice_acceptor_variant ENST00000647841.1
RPS17NR_111943.2 linkuse as main transcriptn.478-1G>A splice_acceptor_variant, non_coding_transcript_variant
RPS17NR_111944.3 linkuse as main transcriptn.185-1G>A splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPS17ENST00000647841.1 linkuse as main transcriptc.156-1G>A splice_acceptor_variant NM_001021.6 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Diamond-Blackfan anemia 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPediatric Oncology and Hematology Unit, National and Kapodistrian University of AthensDec 16, 2022The c.156-1G>A variant in RPS17(NM_001021.6) has been found in a girl with Diamond-Blackfan anemia phenotype and was absent from large population studies. Additionally, family segregation analysis showed that the variant is de novo. The variant is expected to disrupt normal splicing. In summary, this variant meets our criteria to be classified as likely pathogenic, based on the segregation study, absence from controls, and possible aberrant splicing. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.19
Cadd
Pathogenic
26
Dann
Benign
0.97
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
D;D
GERP RS
4.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.77
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.86
Position offset: -23
DS_AL_spliceai
1.0
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-83207737; API